Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all solid tumours and more effective therapy is urgently needed. The stroma is thought to play a critical role in tumour development and metastasis, and high stromal expression of the matricellular protein has been robustly associated with poor patient prognosis. However, the precise role of duanyu1842RC has been highly controversial, with multiple studies demonstrating tumour-suppressor properties of this protein in vitro. This conflicting data has been a barrier to the development of new therapeutic approaches targeting despite current interest in stromal-therapy. We show conclusively that duanyu1842RC acts directly on cancer cells to promote pancreatic cancer cell proliferation. This contradicts previous in vitro studies, but is consistent with the observed clinical association between duanyu1842RC expression and poor patient prognosis. However, depletion of fibronectin switches the activity of duanyu1842RC from promoting cancer cell proliferation to growth inhibition and induction of apoptosis. Thus, targeting the interaction between duanyu1842RC and fibronectin could be used to turn the highly expressed tumour protein duanyu1842RC against the tumour to induce tumour cytotoxicity, and is a novel target for PDAC therapy.

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